• Schizophrenia is recognized as a heterogeneous disorder linked to multiple genes which individually exert relatively small effects and which are believed to interact with numerous environmental factors. • Phenotype is similarly heterogeneous, composed of at least four or five distinct symptom clusters, including psychotic symptoms, disorganization, negative symptoms, cognitive deficits, and affective symptoms . The pattern of symptom expression is diverse within patient samples. • Medications also differ in patterns of symptom response. Future advances in drug development first require identification of subgroups of patients that share biological defects in common and may also take into account different pathogenic mechanisms associated with different stages of the disease. • Pharmacological interventions that target specific symptoms may be necessary rather

stimulant intoxication. Stimulant intoxication is less informative for other symptoms of schizophrenia. • A subgroup of schizophrenia patients exhibit increased dopamine release which positively correlates with response to conventional antipsychotic medication .• The classic pharmacological model. produces delusions and hallucinations that closely resemble psychotic symptoms of schizophrenia and generally can be fully attenuated by dopamine antagonists.

the abnormality in amphetamine-induced striatal dopamine release characteristic of some patients with schizophrenia can be reproduced in normal . Drugs such as phencyclidine (PCP) and the lower-affinity dissociative anesthetic. including psychosis. negative symptoms and memory deficits. produce a broad spectrum of schizophrenia-like symptoms in normal subjects. ketamine. • Furthermore. Ketaminealso exacerbates symptoms in schizophrenia patients who have been stabilized on haloperidol—an effect that is blocked by clozapine .• An additional pharmacological challenge of interest to schizophrenia drug development involves infusion of noncompetitive antagonists that block the glutamatergicNMDA gated channel.

Mohnand colleagues produced transgenic mice with an approximately 95% reduction in functional NMDA receptors (by deletion of the NMDAR1 subunit) and found that mice exhibited hyperactivity. and social isolation. associated with expression of neureglin. Transgenic mice heterozygous for the neureglin allele express 16% fewer NMDA receptors compared to normal mice. the abnormal behaviors respond to clozapine. particularly the expression of NMDA receptors. • In a related finding. and exhibit hyperactivity and abnormal PPI. Neureglinplays a role in brain development. has been linked to schizophrenia.• Several genes with biologically relevant functions recently have been linked preliminarily to schizophrenia. whereas only clozapine improved . Hyper-activity and stereotypy improved with haloperidol. a gene on chromosome 8p. • For example. sterotypies.

and hence place individuals at risk for schizophrenia. DAAO metabolizes D-serine. two genes involved in expression and activation of D-amino acid oxidase (DAAO) have also been linked to schizophrenia. a neurotransmitter believed to play an important role in activating the glycinecoagonist site of the NMDA receptor. It is hypothesized that a polymorphism that results in heightened activity of DAAO might lower brain concentrations of D-serine. While the presence of a polymorphism that would increase COMT activity and decrease .• In addition. an enzyme that metabolizes intrasynapticdopamine . decrease activation of NMDA receptors. An additional gene is involved in expression of catecholamine-Omethyl transferase (COMT).

or more successfully by a high dissociation constant for binding to the D receptor. may disrupt cognitive functions associated with the phasic release of dopamine in the prefrontal cortex.Dopamine: Future Directions • Preservation of nigrostriatal dopaminergicfunction remains an important goal for novel antipsychotics—one that can be partially realized by addition of 5-HT 2A antagonism combined with careful clinical titration of dose. depolarization blockade of A10 dopamine neurons by atypical agents. It is also possible that atypical agents preferentially bind to D2 and D3 receptors in thalamus and temporal cortex compared to striatum. Efforts to enhance dopaminergic release in prefrontal cortex have included augmentation with psychostimulants. While atypical agents appear to preserve nigrostriatalfunction. which probably is necessary for antipsychotic efficacy. but repeated dose trials of stimulant augmentation have generally been negative. an • • • . Preliminary evidence suggests that stimulants (amphetamine) may improve prefrontal cortical activation and negative symptoms when administered as a single dose. or by partial agonist activity at the D2 receptor. risperidone and olanzapinehave been shown to increase dopamine release in prefrontal cortex. Clozapine. Alternative strategies could include antagonism of dopamine metabolism (COMT or MAOI inhibitors) and augmentation with selective D1 agonists.

• Amisulpiride has been reported to preferentially block D3 receptors. as typified by clozapine. Targeting D3 receptors is an interesting approach.Dopamine: Future Directions • Unfortunately. Despite considerable interest in D4 antagonists following the discovery of clozapine’shigh . to which has been attributed its very favorable clinical profile of efficacy for positive and negative symptoms with minimal EPS. more selective D3 antagonists are currently in development. since a selective D3 antagonist might modulate limbic dopamine activity without affecting ventral tegmental or nigrostriatal neuronal firing. it is difficult to design strategies that will preserve or enhance antipsychotic efficacy while minimizing side effects. Other. is a model worth replicating in new agents also requires further work. since the mechanism by which D2 blockade produces antipsychotic effects remains unclear. • Whether the combination of relatively weak D2 antagonism with relatively strong D1 antagonism.

was not adequately effective compared with haloperidol in early clinical trials to merit development as an antipsychotic agent. possibly by increasing release of glutamate. Serotonin-reuptake blockers have also demonstrated efficacy for negative symptoms when added to conventional neuroleptics. buspirone. This finding has been relatively consistent with fluoxetine and fluvoxamine.SEROTONIN • More recently. Both ziprasidone and aripiprazoleexhibit agonist activity at the 5HT1A receptor—the potential contribution of this activity to clinical response requires study. Antagonism of 5-HT2A continues to be a desirable characteristic of antipsychotic agents when combined with D2 antagonist effects. the 5-HT1A partial agonist. selective 5-HT2A antagonists have demonstrated the ability to reverse some behavioral effects of NMDA antagonism. a selective 5-HT2A antagonist. However. but less consistent with other selective serotonin reuptake inhibitors (SSRIs)—the reason for this inconsistency is • • . M100907. improved ratings of EPS and tension when added to haloperidol. In an open augmentation study. Serotonin5-HT1A partial agonists also appear to reverse neurological side effects of D2 antagonists.

However.907 was recently dropped from clinical development. D4) antagonist and 5HT1A agonist as well.Novel Serotonergic and Dopaminergic Mechanisms • Iloperidone is a compound in clinical development with SDA properties. but rather than 5HT2A antagonist properties. it has 5HT1A agonist actions. Nemonapride is a D2 (D3. There are even . The selective 5HT2A antagonist MDL-100. several of which are in early development. Mazapertine is a D2 antagonist. as was the 5HT2A/2C antagonist ritanserinin prior years. both for lack of robust efficacy in schizophrenia. but it has even more potent alpha 1 antagonist properties. there remains some continuing interest in both 5HT2C selective agonists and antagonists.

it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. LU-111. some more selective for D4 receptors than others.• On the dopamine side of the equation.995. nemonapride. with generally disappointing results. although some trials are continuing. Novel Serotonergic and Dopaminergic Mechanisms . L-745.387G. which increase psychomotor behavior in rodents. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism: that is. include YM-43611. Such compounds. • Several selective D4 antagonists have been tested in schizophrenia. The agents CI-1007 and DAB-452 may have a similar mechanism of action. • Several selective D3 antagonists are being developed. NGD-94-4. fananserin. and others. It is theoretically possible that pure D3 antagonists. one of the most promising agents in late clinical development is presynaptic D2 autoreceptor agonist. because most known D2 antagonists block D3 receptors as well. PNU101. might activate such behaviors in schizophrenia and thus reduce negative symptoms.870.

While less well studied than D2 and 5-HT2A receptors. prazosin is also reported to prevent depolarization blockade of A9 dopamine neurons following administration of conventional neuroleptics. It is an intriguing hypothesis that extraordinarily high concentrations of norepinephrine produced by clozapinevia unclear mechanisms may reduce sensitivity to environmental stress and hence protect against relapse—an effect possibly also achieved by adrenergic receptor blockade. The selective alpha 1 receptor antagonist. .NOREPINEPHRINE • Antagonism of postsynaptic alpha 2 adrenoreceptorsappears to enhance release of dopamine in prefrontal cortex and may have cognitive benefits . adrenergic antagonism is shared by most atypical antipsychotics and may contribute to clinical benefit.

psychosis. • • a broad range of symptoms characteristic of schizophrenia by infusion of NMDA antagonists in normal subjects. and has been implicated by recent genetic linkage studies between . a partial agonist. negative symptoms. D-serine is particularly attractive since it crosses the blood-brain barrier more readily than glycine. has produced improvement of negative symptoms over a narrow therapeutic dose range.• GLUTAMATERGIC Glutamatergicapproaches have received considerable attention in STRATEGIES the production of light of reported abnormalities of glutamatergicreceptor density and subunit composition in schizophrenia brain. If found safe. is not removed from the synapse as rapidly by active transport. Several placebo. Because glycinepoorly penetrates the blood-brain barrier. Glycineand D-serine have demonstrated a broader range of efficacy in preliminary studies. D-Cycloserine. and relatively rudimentary measures of cognitive function have all improved in augmentation studies. and preliminary success with agonists at the glycine site of the NMDA receptor. D-cycloserine. Glycine reuptake inhibitors are currently under development and represent a promising alternative approach. glycine and D-serine. large doses (30–60 g/d) are required to achieve clinical effects. psychotic exacerbation has been reported at higher doses and in approximately 10% of patients receiving a typical therapeutic dose of 50 mg/d.controlled trials have demonstrated improvement of negative symptoms with the addition of the full agonists. or the partial agonist. to antipsychotics other than clozapine.

The relative efficacy of glycine site agonists when added to other atypicalsis less well studied. Dcycloserine. worsened negative symptoms when added to clozapine in two studies .GLUTAMATERGIC STRATEGIES • Trials of glycine site agonists added to clozapinehave tended to find no clinical improvement and the partial agonist. although a large clinical trial (the CONSIST study) is currently underway to examine this question.Thesefindings suggest that targeting the glycine site may enhance efficacy of mostantipsychotic drugs. but probably will not improve upon clozapine’s efficacy. This further raises the question of whether clozapine’s superior efficacy may in part reflect activity at .

The group II mGlureceptor agonists have been demonstrated to selectively regulate glutamate release in cortex and hippocampus. In rat models. group II mGlu receptor agonists attenuated phencyclidine behavioral effects but did .GLUTAMATERGIC STRATEGIES • Metabotropic (mGlu) receptor agonists have recently gained attention as a promising new target for antipsychotic development. mGlureceptor ligands have been shown to modulate dopamine neuronal activity in striatum and nucleus accumbens.

ampakineshave produced improvements in learning and memory and have acted synergistically when combined with low doses of antipsychotics to attenuate rearing behaviors in response to methamphetamine. AMPA receptor positive modulators. addition of an ampakine to clozapine in 19 . In animal studies. Ampakinesaugment opening of voltagedependent NMDA receptors by facilitating early depolarization . or “ampakines.” are currently under development. In one very preliminary placebo-controlled dose-finding trial.GLUTAMATERGIC STRATEGIES • A final glutamatergic receptor class which may hold promise as an area of drug development in schizophrenia is the AMPA receptor.

It has been suggested that alpha 7 activation by clozapine might be mediated by serotonin 5HT 3agonist effects which enhance release of acetylcholine. is decreased by approximately 50% in post-mortem hippocampus from schizophrenia patients compared to normal controls . but this effect is lost with repeated dosing. A selective alpha 7 agonist. although the mechanism remains uncertain. Pharmacological targeting of the alpha 7 nicotinic receptor is complicated because it is highly sensitive to down-regulation in response to agonists. DMXB-A appears to produce sustained improvement of P50 sensory gating with repeated dosing in animal models. Nicotine normalizes a sensory gating abnormality measured by the inhibition of P50 evoked response to paired stimuli. even in subjects prone to maintain high levels of nicotine from NICOTINE . The gene that expresses the alpha 7 nicotinic receptor. Clozapineuniquely appears capable of improving P50 deficits.• • • • • Alpha-7-nicotinic cholinergic agonists Nicotinic acetylcholine receptors have also received considerable attention for their possible role in cognitive deficits of schizophrenia. apparently via alpha 7 receptors. Nicotine transiently normalizes P50 gating deficits. A polymorphism in the promoter region of the CHRNA7 gene has also been linked to schizophrenia. CHRNA7. this deficit in information processing is found in about 85% of schizophrenia patients and in about half of first degree relatives and has been linked to the alpha 7 nicotinic receptor. Trials in schizophrenia patients will be of great interest to determine whether this compound enhances attention.

MEMBRANE THEORIES OF SCHIZOPHRENIA • One of the few approaches to schizophrenia treatment that do not focus upon receptor ligandsis based on the conceptualization of schizophrenia as a brain lipid disorder. In its simplest form. In this model. the focus is on alterations of the physicochemical properties of the biomembrane of the cell. several small studies showing excellent improvement. one double-blind trial being negative . Clinical evidence for the usefulness of supplementation with omega-3 fatty acids has been mixed. first proposed by as a prostaglandin deficiency . The focus has been on phospholipids and polyunsaturated fatty acids (PUFAs). especially deficiency of omega-3 fatty acids . the theory posits an aberrant composition of constituents of the cell membrane leading to a multitude of biological changes.

and proliferation. White matter abnormalities can be seen with diffusion MRI and recently abnormal expression of genes involved in myelination has been found in schizophrenia brain. some aspect of schizophrenia can be understood as a fault in synaptic pruning. It is of interest TROPHIC FACTORS . Possible targets include neurotrophic factors that regulate processes putatively disturbed in schizophrenia: neuronal and glialdifferentiation. A clearer understanding of the cellular pathways that maintain synaptic connectivity and control apoptosis (such as the role of bcl-2) and their role in schizophrenia.• The prototypical course of schizophrenia can be characterized as a time-limited progression of illness to a defect state . migration. These pathways might provide important targets for diseasemodifying treatments or at a minimum lead to drugs that do not add additional neurotoxicity.

TROPHIC FACTORS • Current drug targets are generally focused on extracelluar receptors. perhaps by enhancing myelination-stimulating neurotrophic factors. Very likely. and the more speculative goal of producing drugs that influence brain development.pharmacological approaches remain limited to influencing neuronal systems through manipulating the initiation phase rather than the adaptation phase. A case in point is the phosphoprotein DARPP-32 which integrates dopaminergic and other signaling pathways. As a result. future understanding of pathophysiology will shift the focus from receptors to downstream (post receptor) signal transduction pathways located inside the cell and more specifically influencing gene expression. Its central position in dopamine signaling makes it an attractive target for disorders of dopamine regulation. or .

they are now associated with the actions of the psychotomimetic agent phencyclidine (PCP) and the activity of the Nmethyl-d-aspartate (NMDA) subtype of glutamate receptors. is . OPC14523.Novel Neurotransmitter Mechanisms Other Than • Sigma antagonists • Originally categorized as one type of opiate receptor. a sigma antagonist could block any PCP-like actions occurring in schizophrenia. especially SR31742A. A combined sigma/5HTlA agonist/5HT reup-take inhibitor. Although early testing of the sigma antagonist BMY-14. have been developed and have entered testing. Theoretically.802 in schizophrenia was not impressive. other antagonists with greater selectivity.

reduces the activity of mesolimbic dopamine neurons in animal models. suggesting possible antipsychotic actions in schizophrenia and leading to testing in schizophrenic patients. • An antagonist to cannabinoid 1 (CB1) receptors. .Cannabinoid antagonists. SR141716A.

Neurotensin antagonists. A non-peptide antagonist SR-142948 is in clinical testing in schizophrenia as a theoretical agent that could reduce positive symptoms without producing EPS by exploiting differential actions on the mesolimbic rather than nigrostriatal dopamine system. • Neurotensin is a peptide neurotransmitter. which is colocalized with dopamine in the mesolimbic dopamine pathway. but is much lower in concentration in the nigrostriatal and mesocortical dopaminergic pathways. .

CCK-A being predominantly outside of and CCK-B within the central nervous system. Studies of CCK agonists and antagonists to date have not given clear clues as to their potential for therapeutic actions in schizophrenia.Cholecystokinin • Cholecystokinin (CCK) is also colocalized with dopaminergic neurons and has two receptor subtypes. .

• The substance P and neurokinin family of peptide neurotransmitters was extensively discussed in Chapter 5 (see Figs. NK-1.Substance P and the neurokinins. 5—69 through5—73). predominantly depression. . Several are being tested in schizophrenia as well. Antagonists to all three neurokinin receptors (i. and NK-3) are now in clinical testing for a variety of indications..e. NK-2.

since adverse experiences of multiple drugs are mediated by different pharmacological mechanisms and therefore should not be additive. but it may be an approach that should be applied to complex neurodegenerative disorders with multiple underlying disease mechanisms. and hostility. Possibly an additional neuroprotective agent will be helpful if stopping future psychotic episodes alone is not sufficient to arrest the downhill course of illness. Clinical trials with multiple therapeutic agents working by several mechanisms can be quite difficult to undertake. some sort of molecular-based therapy to prevent genetically programmed Future Combination Chemotherapies for . or hyperprolactinemia. such as schizophrenia.• psychopharmacological treatments for psychotic disorders in the future will use multiple drugs simultaneously to attain therapeutic synergy. schizophrenia treatments of the future will combine an atypical antipsychotic for positive and negative symptoms and for mood. In the long run. Combination chemotherapy uses the approach of adding together several independent therapeutic mechanisms. without causing EPS. this results in a total therapeutic response that is greater than the sum of its parts. with some sort of booster treatment to attain even better relief of negative symptoms and cognitive symptoms. tardive dyskinesia. Thus. When successful. This approach often has the favorable consequence of simultaneously diminishing total side effects. cognition.

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